Continuous ambulatory peritoneal dialysis (CAPD) is used to treat end stage renal failure (ESRF) by introducing an osmotically active solution into the peritoneal cavity. Toxic waste products and excess fluid move from the blood into the dialysate solution by diffusion and ultrafiltration across the peritoneum. Osmotic ultrafiltration occurs as a result of the addition of hypertonic concentration of glucose to the dialysing solution, Due to the osmotic gradient between the blood and the CAPD solution the glucose draws water from the blood stream into the peritoneal cavity. The osmotic effect is transient and diminishes as the glucose is absorbed and/or metabolised.
In CAPD the dialysis solution is infused from collapsible plastic bags into the peritoneal cavity where it is retained for a period of time (referred to as the dwell time), after which it is drained and discarded. Generally, 3-5 treatments or exchanges of 1-3 liters each of CAPD solution are carried out daily, with an overnight dwell. The glucose concentration varies between 1.5 and 5% (w/v), with commercial CAPD solutions containing 1.5%, 2.5 or 4.5% glucose, with a high lactate content and various electrolytes which are present in more or less pH ysiologic concentrations. CAPD patients also lose 5-10 grams of protein into the dialysate per day. Commercial CAPD solutions typically have an osmolarity of 300-700 mOsm/L, preferably 350-450 mOsmol/L, as taught by U.S. Pat. No. 5,011,826.
Although peritoneal dialysis has some advantages over hemodialysis, including a substantial cost saving, there are several potential complications to CAPD. These include protein loss through the relatively highly permeable peritoneal membrane, absorption and metabolism of the added glucose resulting in weight gain and hyperlipidemia, which is particularly problematic in diabetic patients, who have a high incidence of ESRF (Ong-Ajyooth, L., Transp Proc 26: 2077, 1994).
An average patient absorbs about 150 grams of glucose from the dialysate per day, which for many patients is an excessive source of carbohydrate and results in hyperinsulinemia and hypertriglyceridemia in non-diabetic patients, which contributes to atherosclerotic disease. This series of events likely contributes to cardiovascular disease which is the most common cause of death among patients with ESRF.
Chronic exposure of the peritoneal membrane to the hypertonic and acidic CAPD solution (pH 5-6.2)can result in a loss of its function as an ultrafiltration membrane, leading to increased permeability of the peritoneal membrane and an increased rate of absorption of glucose from the dialysis solution and a loss of ultrafiltration capability. (Breborowicz et al Advances in Peritoneal Dialysis 8: 11, 1192 and Breborowicz et al Nephron 67: 350, 1994). Peritoneal biopsy samples from patients chronically dialysed with CAPD solutions show a typical epithelial reaction to irritation, mesothelial cell proliferation, as well as a decrease in the number of microvilli which normally line the mesothelial cell surface (Dobbie, J. W., Lloyd, J. K., Gall, C. A. In R. Khamma, K. D. et al Eds. Advances in peritoneal dialysis. Toronto. U of Toronto Press, 3, 1990: Friedlander, M. J Lab Clin Med 122: 639, 1993). A chronic inflammation of the peritoneum is also a consequence of chronic CAPD treatment, possibly related to the acidic nature of the CAPD solution (Lewis, S. and Holmes, C. Periton Dial Int 11: 14, 1991; Beelen, R. H. J. et al In Maher J. F., Winchester, J. F. Eds. Frontiers in peritoneal dialysis. New York: Field, Richj and Associates, 524, 1986; Bos, H. J. et al Nephron 59: 508, 1991), and which leads to healing (Weiczorowska, K. et al. Perit. Dial. Int. 15:81, 1995). Morphologic changes in the peritoneal structure also occur with chronic CAPD therapy, including fibrosis of the peritoneum (Chaimovitz, C., Kidney Int 45: 1226, 1994). Further, the use of the current relatively acidic and glucose hypertonic CAPD solutions results in a decrease in the function of peritoneal macrophages, again indicating a need for more physiologic and biocompatible CAPD solutions (deFijter, C. W. H. et al Clin Nephrology 39: 75, 1993).
As well, it has been shown that there is a loss of glycosaminoglycans (GAG""s) from the peritoneal membrane which results in a loss of filtration efficiency. It has been suggested that the loss of GAG""s from the peritoneal membrane is a result of the increased production of free radicals by activated peritoneal leukocytes (Breborowicz, A. et al Periton Dial Int 11 (Suppl): 35a, 1991) or because of a destructive action on interstitial tissue proteins (Fligiel, S. E. G. et al Amer J Pathol 115: 418, 1984). Supplementation of the dialysis fluid with the GAG chondroitin sulphate increases net ultrafiltration due to slower absorption of glucose and fluid from the peritoneal cavity (Advances in Peritoneal Dialysis 8: 11, 1992; Nephron 67: 346, 1994), possibly due to its ability to scavenge free radicals. Other GAG""s, such as heparin and dermatan have also been reported to scavenge free radicals (Hiebert, L., Liu, J. M., Semin Thromb Hemost 17: 42, 1991; Fracasso, A. et al J Amer Soc Neph 5: 75p, 1994). It has also been reported that hyaluronan (formerly known as hyaluronic acid), which also scavenges free radicals, protects the peritoneum from injury resulting from CAPD treatment (Wieczorowska, K. et al Perit. Dial. Int. 15:81, 1995). Supporting this is the finding that the dialysis fluid collected overnight has a higher concentration of hyaluronan than serum. For example, Yung, S. et al (Kidney Int 46: 527, 1994) found that hyaluronan levels increased in the dialysate from ESRF patients with or without peritonitis undergoing CAPD treatment, and that the peritoneal mesothelial cells were the likely source of the hylauronan. Hyaluronan is important in the regulation of cell proliferation during healing. Hyaluronan is a polymer of repeating molecules of N-acetylglucosamine and glucuronic acid; dermatan is composed of repeating units of N-acetylglucosamine and iduronic acid, and chondroitin is made up of glucuronic acid and N-acetylgalactosamine.
Breborowicz and Oreopulos have submitted a PCT patent application (EP-555087-A1) (priority 92US-830721) for the addition of free radical scavengers such as GAG""s, including hyaluronic acid degradation products, to CAPD solutions during episodes of peritonitis to prevent against peritonitis-associated inflammatory reactions.
As noted above, N-acetylglucosamine (NAG) is a component of many GAG""s. NAG is formed in almost all cells from glucose through a series of biochemical reactions which include the addition of the amine group from glutamine to glucose to form glucosamine, with N-acetylglucosamine being synthesized by way of acetyl-CoA. NAG then is converted to NAG-6-phosphate (which is converted into the epimer of NAG, N-acetyl-mannosamine 6-phosphate which is converted to N-acetylneuraminic acid 9-phosphate which is incorporated into sialic acids, gangliosides and glycoproteins ), to NAG-1-phosphate (which is converted into UDP-N-acetylglucosamine (UDP-NAG) which is incorporated into GAG""s such as chondroitins and glycoproteins). The UDP-NAG is also converted into GAG""s such as hyaluronan and glycoproteins. Thus, NAG is the primary building block of many essential tissue components, whether they are comprised of NAG itself or related amino sugars such as N-acetylmannosamine and N-acetylgalactosamine.
It has been shown that orally administered glucosamine and N-acetylglucosamine (NAG) are absorbed and distributed throughout the body rapidly, and incorporated into tissues and presumably into the GAG""s of the body. These compounds are incorporated into the GAG""s of the peritoneal membrane to prevent their depletion thus maintaining the integrity of the peritoneal membrane, and preventing or at least slowing down, the loss of membrane function as an ultrafiltration membrane. Thus, the replacement of part or all of the glucose in the presently available CAPD solutions with amino sugars, especially NAG, should provide a more biocompatible peritoneal dialysis solution, while providing the necessary osmotic effect required for the removal of excess water and also removal of waste substances by solvent drag from patients with ESRF undergoing CAPD treatment. Unlike glucose, which is utilized by almost all microorganisms as a source of energy, the amino sugars are relatively less metabolized and not as likely to support microbial growth thus reducing the tendency for patients undergoing chronic CAPD treatment to develop peritonitis, a common and serious adverse event associated with CAPD treatment. Because of the rapid removal of NAG and other amino sugars from the systemic circulation by way of their incorporation into GAG""s and various amino sugar containing tissue components the extent of metabolism into lipids is significantly reduced, thus reducing the risk of obesity, protein malnutriton, dyslipidemia and hypertriglyceridemia, hyperinsulinemia etc and the related adverse metabolic consequences.